CN1649862A - Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics - Google Patents
Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics Download PDFInfo
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- CN1649862A CN1649862A CNA038094606A CN03809460A CN1649862A CN 1649862 A CN1649862 A CN 1649862A CN A038094606 A CNA038094606 A CN A038094606A CN 03809460 A CN03809460 A CN 03809460A CN 1649862 A CN1649862 A CN 1649862A
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- compound
- alkyl
- ethyl
- acceptable salt
- tetrazolium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
Thus, the present invention provides compounds of formula (I) The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a neurological disorder. The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain or migraine.
Description
Technical field
The present invention relates to (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the novel prodrug forms of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, the pharmaceutical composition that contains this prodrug forms and application contain the method for this prodrug forms.
Background technology
United States Patent (USP) 5,670,516 some Decahydroisoquinolinpreparation derivative of disclosure are ampa receptor antagonists, are used for the treatment of many different disorders, comprise pain and migraine.In addition, January 11 calendar year 2001, disclosed WO 01/02367A3 disclosed selectivity GluR
5Antagonist 3S, 4aR, 6S, 8aR-6-(((4-caxboxy) phenyl) methyl)-1,2,3,4,4a, 5,6,7,8, the diester prodrug forms of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid.
An object of the present invention is to provide (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the monoesters of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, it has improved female medicine monoprotic acid in the intravital bioavailability of patient.Another object of the present invention provide (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the monoesters of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, it is converted into female medicine monoprotic acid basically in patient's body.
Summary of the invention
Have found that, itself compare with the monoprotic acid of using, (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the novel monoesters of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid can significantly improve monacid bioavailability.In addition, monoesters is converted into monoprotic acid basically in patient's body.US5,670,516 (announcements on September 23rd, 1997) disclose described monoprotic acid.
Like this, the invention provides formula I compound or pharmaceutically acceptable salt thereof:
Formula I
Wherein R represents C
1-C
20Alkyl, C
2-C
6Alkenyl, C
1-C
6Alkylaryl, C
1-C
6Alkyl (C
3-C
10) cycloalkyl, C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine, C
1-C
6Alkyl-tetramethyleneimine, C
1-C
6Alkyl-piperidines, C
1-C
6Alkyl-morpholine.
The present invention further provides antagonism AMPA or GluR
5The method of acceptor comprises that the formula I compound with significant quantity gives the patient.
In addition, the present invention further provides the method that is used for the treatment of neurological disorder (neurologicaldisorder), comprise the patient who the formula I compound of significant quantity is given this is had needs.
The present invention further provides and be used for the treatment of pain or migrainous method, comprise the patient who the formula I compound of significant quantity is given this is had needs.
The present invention further provides formula I compound and be used for the treatment of application in the medicine of neurological disorder in preparation.
The present invention further provides formula I compound and be used for the treatment of application in pain or the migrainous medicine in preparation.
Detailed Description Of The Invention
Be meant the monoester derivates of carboxylic acid function's property medicine at this used term " prodrug ", described derivative gives to be converted into monoprotic acid (medicine) behind the patient.The compounds of this invention discharges parent monocarboxylic acid (medicine) with enzymatic and/or chemical hydrolysis cracked mode.
Be meant at this used term " compd A " (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid.
Be meant 6-[2-(2H-tetrazolium-5-yl) ethyl at this used term " compd B "]-decahydro-ethyl isoquinoline-3-carboxylate.
Be meant 6-[2-(1H-tetrazolium-5-yl) ethyl at this used term " Compound C "]-decahydro-isoquinoline 99.9-3-carboxylic acid 2-ethyl-butyl ester.
Be meant 6-[2-(1H-tetrazolium-5-yl) ethyl at this used term " Compound D "]-decahydro-isoquinoline 99.9-3-carboxylic acid isobutyl.
Be meant 6-[2-(2H-tetrazolium-5-yl) ethyl at this used term " compd E "]-decahydro-isoquinoline 99.9-3-carboxylic acid 3-methyl-butyl ester.
Be meant 6-[2-(1H-tetrazolium-5-yl) ethyl at this used term " compound F 17-hydroxy-corticosterone "]-decahydro-isoquinoline 99.9-3-carboxylic acid decyl ester.
At this used term " C
1-C
4Alkyl " be to retouch straight or branched, monovalence, the saturated aliphatic chain that contains 1-4 carbon atom, include but not limited to methyl, ethyl, n-propyl group, sec.-propyl, n-butyl, isobutyl-etc.
At this used term " C
1-C
6Alkyl " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, include but not limited to methyl, ethyl, n-propyl group, sec.-propyl, n-butyl, isobutyl-, the tertiary butyl, n-amyl group, n-hexyl etc.Be understandable that term " C
1-C
4Alkyl " be included in " C
1-C
6Alkyl " definition within.
At this used term " C
1-C
10Alkyl " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-10 carbon atom; include but not limited to methyl, ethyl, n-propyl group, sec.-propyl, n-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, 2; 3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-amyl group, 2-methyl-2-hexyl, octyl group, 4-methyl-3-heptyl etc.Be understandable that term " C
1-C
4Alkyl " be included in " C
1-C
10Alkyl " definition within.
At this used term " C
1-C
20Alkyl " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-20 carbon atom, include but not limited to methyl, ethyl, n-propyl group, sec.-propyl, n-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, 3-methyl amyl, 2-ethyl-butyl, n-heptyl, n-octyl group, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl etc.Be understandable that term " C
1-C
4Alkyl ", " C
1-C
6Alkyl " and " C
1-C
10Alkyl " be included in " C
1-C
20Alkyl " definition within.
Be meant methyl, ethyl, propyl group, sec.-propyl, butyl and tert-butyl respectively at this used " Me ", " Et ", " Pr ", " iPr ", " Bu " and " t-Bu ".
At this used term " C
2-C
6Alkenyl " be meant the straight or branched, the monovalence unsaturated fatty chain that contain 2-6 carbon atom.Typical C
2-C
6Alkenyl comprises ethylidine (being vinyl), 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 1-butylene base, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, crotyl, pentenyl etc.
Be meant that at this used term virtue " aryl " comprising one or more condenses or the monovalence carbocyclic ring of non-condensed phenyl ring, comprises for example phenyl, 1-or 2-naphthyl, 1,2-dihydro naphthyl, 1,2,3,4-tetralyl etc.
At this used term " C
1-C
6Alkyl-aryl " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, wherein aryl links to each other with aliphatic chain.Term " C
1-C
6Alkyl-aryl " comprising:
At this used term " (C
3-C
10) cycloalkyl " be meant the stable hydrocarbon ring structure that contains 3-10 carbon atom.Typical C
3-C
10Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.Be understandable that " (C
3-C
8) cycloalkyl " and " (C
4-C
6) cycloalkyl " be included in term " (C
3-C
10) cycloalkyl " within.
At this used term " C
1-C
6Alkyl-(C
3-C
10) cycloalkyl " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, wherein (C
3-C
10) cycloalkyl links to each other with aliphatic chain.Term " C
1-C
6Alkyl-(C
3-C
10) cycloalkyl " comprising:
At this used term " N, N-C
1-C
6Dialkylamine " be meant by two and contain the straight or branched of 1-6 carbon atom, the nitrogen-atoms that the monovalence saturated aliphatic chain replaces.Term " N, N-C
1-C
6Dialkylamine " comprise-N (CH
3)
2,-N (CH
2CH
3)
2,-N (CH
2CH
2CH
3)
2,-N (CH
2CH
2CH
2CH
3)
2Deng.
At this used term " C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, N wherein, N-C
1-C
6Dialkylamine links to each other with aliphatic chain.Term " CC
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine " comprising:
At this used term " C
1-C
6Alkyl-tetramethyleneimine " be meant the straight or branched, the monovalence saturated aliphatic chain that contain 1-6 carbon atom, wherein tetramethyleneimine links to each other with aliphatic chain.Term " C
1-C
6Alkyl-tetramethyleneimine " comprising:
At this used term " C
1-C
6Alkyl-piperidines " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, wherein piperidines links to each other with aliphatic chain.Term " C
1-C
6Alkyl-piperidines " comprising:
At this used term " C
1-C
6Alkyl-morpholine " be meant the straight or branched, monovalence, the saturated aliphatic chain that contain 1-6 carbon atom, wherein morpholine links to each other with aliphatic chain.Term " C
1-C
6Alkyl-morpholine " comprising:
The compounds of this invention comprises known tetrazole ring with tautomeric structure.Have two keys and the tetrazolium called after 2H tetrazolium of hydrogen on the nitrogen-atoms of 2-position at 1-position nitrogen-atoms, its structure is:
Its corresponding tautomeric form (hydrogen on 1 nitrogen-atoms and two keys on 4-position nitrogen is former) called after 1H-tetrazolium.The 1H-tetrazolium is shown below:
The mixture of two kinds of tautomers is meant 1 (2) H-tetrazolium at this.The present invention includes the combination of tautomeric form and two kinds of tautomers.
Sign
Be meant key by the outside projected direction of paper plane.
Sign
Be meant the key that stretches to the paper plane direction.
The present invention includes the hydrate and the pharmacologically acceptable salt of formula I compound.The compounds of this invention has enough basic functionalities, can form pharmacologically acceptable salt with any inorganic and organic acid reaction.
Be meant salt at this used term " pharmacologically acceptable salt " to the nontoxic basically formula I compound of biological organism.Typical pharmacologically acceptable salt comprises The compounds of this invention and medicinal inorganic or salt that organic acid reaction is prepared.Such salt is acid salt.
The acid that is generally used for forming acid salt is mineral acid, for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid etc.; With organic acid for example p-toluenesulphonic acids, methylsulfonic acid, oxalic acid, p-bromobenzene sulfonic acid, carbonic acid, succsinic acid, citric acid, phenylformic acid, acetate, trifluoroacetic acid etc.Being exemplified as of this pharmacologically acceptable salt: vitriol, pyrosulphate, hydrosulfate, sulphite, bisulfite, phosphoric acid salt, hydrogen phosphate (monohydrogenphosphate), dihydrogen phosphate, metaphosphate, pyrophosphate salt, bromide, iodide, acetate, trifluoroacetate, propionic salt, caprate octylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, hexanoate, enanthate, propionic salt, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diacid salt, hexin-16-diacid salt, benzoate, chloro-benzoate, tolyl acid salt, hydroxybenzene hydrochlorate, methoxybenzoic acid salt, phthalate, xylenesulfonate, phenylacetate, phenylpropionic acid salt, phenylbutyric acid salt, citrate, lactic acid salt, α-hydroxybutyric acid salt, oxyacetate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate etc.Preferred medicinal acid addition salt is and the salt of mineral acid (for example hydrochloric acid and Hydrogen bromide) formation and the salt that forms with organic acid (for example toxilic acid, oxalic acid, trifluoroacetic acid and methylsulfonic acid).
Be understandable that, usually do not possess decisive performance by the formed any part of specific counter ion (counterion) in the salt of the present invention, needing only described salt itself is that pharmacology is acceptable and as long as these counter ion itself bring unwanted character for described salt.Will be further appreciated that the form that this salt can hydrate exists.
Be meant the compound that is made of through the different three-dimensional structures of same keys bonded same atoms at this used term " steric isomer ", these three-dimensional structures are not interchangeable.This three-dimensional structure is known as configuration." enantiomorph " is meant that molecule is each other the mirror image relation but 2 kinds of steric isomers of the unanimity (nonsuperimposable) that can not overlap each other at this used term.Term " chiral centre " is meant and is connected with 4 kinds of not isoplastic carbon atoms." diastereomer " is meant the steric isomer that is not enantiomorph at this used term.In addition, having not on a chiral centre, 2 kinds of diastereomers of isomorphism type are meant " epimer " at this.Term " racemoid ", " racemic mixture " or " racemic modification " are meant the mixture of equal portions enantiomorph.
" enantiomorph enrichment (enrichment) " is meant the increase of the amount of an enantiomorph with respect to another enantiomorph at this used term.A kind ofly represent that the facilitated method of enantiomorph enrichment is enantiomeric excess or " ee " notion, adopt following formulate:
E wherein
1Be the amount and the E of first enantiomorph
2It is the amount of second enantiomorph.Like this, for example in racemic mixture,,, show that then it is 25% that first enantiomorph divides ee when the enantiomorph enrichment is enough to produce 50: 30 final ratio if the initial ratio of 2 kinds of enantiomorphs is 50: 50.Yet if final ratio is 90: 10, the ee of first enantiomorph is 80%.Preferred ee is greater than 90%, most preferably ee greater than 95% and especially most preferably ee greater than 99%.Adopt standard technique and method (gas phase or the high performance liquid chromatography that for example have chiral column), those of ordinary skills are easy to measure the enantiomorph enrichment.Chiral column, eluent and effective enantiomer separation that those of ordinary skills are easy to select to suit are to required condition.In addition, adopt standard technique known in the art, J.Jacques etc. " enantiomorph, racemoid and the fractionation " described for example, John Wiley and Sons company, 1981 years, the enantiomorph of those of ordinary skills' detachable I compound.
The compounds of this invention has one or more chiral centres, and may exist with various stereoisomers configurations.Owing to have these chiral centres, The compounds of this invention exists with racemoid, mixture of enantiomers and independent enantiomorph and diastereomer and non-enantiomer mixture form.All these class racemoids, enantiomorph and diastereomer are within the scope of the present invention.
Be meant the term of the particular configuration that is used to define chiral centre in the organic chemistry at this used term " R " and " S ".Term " R " (right side) is meant that when the minimum group of ordering is placed on from viewer's eyes position farthest the ordering (ordering maximum → ordering second is little) of observing all the other groups in the chiral centre configuration is clockwise direction.Term " S " (left side) is meant that when the minimum group of ordering is placed on from viewer's eyes position farthest the ordering (ordering maximum → ordering second is little) of observing all the other groups in the chiral centre configuration is counterclockwise.The ordering size of group depends on its ordination number (with the ordination number rank order of successively decreasing).About the part that ordering and stereochemistry are discussed is tabulated, can be referring to " Nomenclature of OrganicCompounds:Principles and Practice " editors such as (, 1974) J.H.Fletcher 103-120 page or leaf.
Adopt known technology and method, for example Eliel and Wilen, " Stereochemistryof Organic Compounds ", John Wiley Sons company, 1994, the 7th chapter, Separation of stereoisomers.Resolution.Racemization; And Collet and Wilen, Enantiomers, Racemates, and Resolutions ", John Wiley ﹠amp; Sons company, 1981, particular stereoisomer and enantiomorph that those of ordinary skills can preparation formula (I) compound.For example, adopt enantiomorph and how much (enriched) starting materials pure or enantiomorph or how much enrichments, can make particular stereoisomer and enantiomorph through stereoselective total synthesis.In addition, adopt the chromatography, enzymatic fractionation or the part recrystallization technology that for example the additive salt that is formed by suitable reagent are carried out chiral stationary phase, detachable steric isomer and the enantiomorph specific with recovery.
Those of ordinary skills adopt routine techniques and method to be easy to make formula I compound.More particularly, for example can be according to the synthetic route shown in the following route through the chemical process preparation I compound.Yet, below discuss should not be considered as limiting the scope of the present invention.For example, the specific synthesis step of route described here can be the combination of the different methods of preparation I compound.Unless refer else, all substituent definition as mentioned above.Those of ordinary skills are easy to obtain described reagent and starting material.For example, those of ordinary skills can adopt United States Patent (USP) 5,356,902 (announcements on October 18th, 1994) and 5,446,051 (announcements on August 29 nineteen ninety-five) and 5,670,516 (announcement on September 23rd, 1997) disclosed method prepares some starting material, and all disclosures of above-mentioned patent are hereby incorporated by.Employing is selected from the similar techniques of analogue compounds of organic and heterocyclic chemistry standard technique, synthetic known structure and the method for the method (comprising any novel method) that embodiment describes, and can make other reagent and starting material required in the following technology.
Route I
Compd A
Formula I
In route I, under standard conditions known in the art, the esterified accepted way of doing sth I monoesters of compd A.For example, compd A is dissolved in the suitable organic solvent, and with for example salt acid treatment of suitable acid.The example of suitable organic solvent comprises: methyl alcohol, ethanol, propyl alcohol, Virahol, n-butanols, isopropylcarbinol, the trimethyl carbinol, amylalcohol, primary isoamyl alcohol, hexanol, 3-methyl amyl alcohol, 2-ethyl butanol, n-enanthol, n-octanol decyl alcohol etc.React on about 40-60 ℃ of heating about 4-16 hour.Separated product then, and for example abstraction technique and chromatography are carried out purifying to adopt those of ordinary skills' technology.
For example, after the above-mentioned reaction cooling,,,, filter under the vacuum and concentrate, obtain formula I compound through anhydrous magnesium sulfate drying with saturated sodium bicarbonate, normal saline washing with for example ethyl acetate dilution of suitable organic solvent.Can adopt quick silica gel chromatography (suitable eluent ethyl acetate/hexane), the gained material is further purified.
In addition, also compd A can be dissolved in the organic solvent and with excessive thionyl chloride and handle.The example of suitable organic solvent comprises: anhydrous methanol, ethanol, propyl alcohol, Virahol, n-butanols, isopropylcarbinol, the trimethyl carbinol, amylalcohol, primary isoamyl alcohol, hexanol, 3-methyl amyl alcohol, 2-ethyl butanol, n-enanthol, n-octanol decyl alcohol etc.Solution was in reflux temperature stir about 1-3 hour and at room temperature stir about 8-16 hour.Mixture concentrates under vacuum then, according to being similar to aforesaid method purifying residue, obtains formula I monoesters prodrug.
Adopt routine techniques and method, those of ordinary skills are easy to make the pharmacologically acceptable salt of formula I compound.For example, above-mentioned product is suspended in the saturated ether of HCl gas.Mixture stir about 1-3 hour.Filtering precipitate then, and under vacuum with the ether flushing, obtain the pharmacologically acceptable salt of formula I monoesters prodrug.
The typical case that following examples have been described above-mentioned formula I compound synthesizes.These embodiment are intended to explanation, and the present invention is acted on without limits.Those of ordinary skills are easy to obtain described reagent and starting material.Have following implication in this used following term: " eq " or " equiv. " is meant equivalent; " g " is meant gram; " mg " is meant milligram; " L " is meant liter " mL " be meant milliliter; " pL " is meant that " " mol " is meant mole to microlitre; " mmol " is meant that mmole " psi " is meant pound/square inch; " min " is meant minute; " h " is meant hour; " ℃ " be meant centigradetemperature; " TLC " is meant thin-layer chromatography; " HPLC " is meant high performance liquid chromatography; " δ " is meant the chemical shift of representing with ppm (is reference substance with the tetramethylsilane); " THF " is meant tetrahydrofuran (THF); " DMF " is meant N, dinethylformamide; " DMSO " is meant methyl-sulphoxide; " aq " is meant water-based; " EtOAc " is meant ethyl acetate; " iPrOAc " is meant Iso Butyl Acetate; " MeOH " is meant methyl alcohol; " MTBE " is meant that methyl tertiary butyl ether and " RT " are meant room temperature.
Embodiment 1
6-[2-(1H-tetrazolium-5-yl)-ethyl]-decahydro-isoquinoline 99.9-3-carboxylic acid 2-ethyl-butyl ester
To the 6-[2-of the 2.5g (8.4mmol) in 20ml 2-ethyl-1-butanols (1H-tetrazolium-5-yl)-ethyl] and decahydro-isoquinoline 99.9-3-carboxylic acid mono-hydrate (press J.Med.Chem., 39 (11), 2232-2244 page or leaf, 1996 years; Or September in 1997 23 US5 that announces, 670,516 description preparation) solution in, add 6.8ml (92.8mmol) thionyl chloride.Solution stirred 3 hours in 120 ℃.The mixture vacuum concentration, and wash residue with diethyl ether.Residue obtains title compound through SPE (Oasis HLB) purifying.
Electrospray mass spectrum: M+1=364
Embodiment 2
6-[2-(1H-tetrazolium-5-yl)-ethyl-decahydro-isoquinoline 99.9-3-carboxylic acid isobutyl
Basically press embodiment 1 described method preparation, adopt 20mL 2-methyl isophthalic acid-propyl alcohol, obtain title compound.
Electrospray mass spectrum: M+1=336
Embodiment 3
6-[2-(2H-tetrazolium-5-yl)-ethyl]-decahydro-isoquinoline 99.9-3-carboxylic acid 3-methyl-butyl ester
Basically according to embodiment 1 described method, adopt 20mL 3-methyl isophthalic acid-butanols, obtain title compound.
Electrospray mass spectrum: M+1=350
Embodiment 4
6-[2-(the 1H-ethyl]-decahydro-isoquinoline 99.9-3-carboxylic acid ester in the last of the ten Heavenly stems
In 120 ℃, will be at 2.5g (8.4mmol) 6-[2-(1H-tetrazolium-5-the yl)-ethyl in the 50ml decyl alcohol (HCl gas is saturated)]-decahydro-isoquinoline 99.9-3-carboxylic acid mono-hydrate solution heated overnight.The mixture vacuum concentration, residue obtains title compound through SPE (Oasis HLB) purifying.
Electrospray mass spectrum: M+1=420
Embodiment 5
6-[2-(the 2H-ethyl]-decahydro-ethyl isoquinoline-3-carboxylate
In reflux temperature, will be at 6.0g (21.5mmol) 6-[2-(1H-tetrazolium-5-the yl)-ethyl in the 70ml ethanol (hydrogen chloride gas is saturated)]-decahydro-isoquinoline 99.9-3-carboxylic acid mono-hydrate solution heated overnight.The mixture vacuum concentration, and be suspended in the ether, carry out vacuum concentration again.Residue is suspended in the ether, and reflux 3 hours.Cross filter solid, and use ether rinse, obtain 7.4g (100%) title compound.
Electrospray mass spectrum: M+1=308
The particular aspects of formula I compound:
Several groups of specified substituent of formula I compound have been listed below.Be understandable that, possess this special substituent formula I compounds represented special aspect of the present invention.Will be further appreciated that these groups can with other given moiety combinations, constituted other special aspects of the present invention.
Like this, the special aspect of novel compounds of formula I comprises:
(a) R represents C
1-C
20Alkyl, C
2-C
6Alkenyl, C
1-C
6Alkyl-aryl, C
1-C
6Alkyl-(C
3-C
10) cycloalkyl, C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine, C
1-C
6Alkyl-tetramethyleneimine, C
1-C
6Alkyl-piperidines, C
1-C
6Alkyl-morpholine;
(b) represent C
1-C
10Alkyl or C
2-C
6Alkenyl;
(c) represent C
1-C
10Alkyl or C
1-C
6Alkyl-aryl;
(d) represent C
1-C
10Alkyl or C
1-C
6The cycloalkyl of alkyl-(C3-C10);
(e) represent C
1-C
10Alkyl or C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine;
(f) represent C
1-C
10Alkyl or C
1-C
6Alkyl-tetramethyleneimine;
(g) represent C
1-C
10Alkyl or C
1-C
6Alkyl-piperidines;
(h) represent C
1-C
10Alkyl or C
1-C
6Alkyl-morpholine;
(i) R represents C
1-C
10Alkyl;
(j) R represents 2-ethyl-butyl, isobutyl-, 3-methyl butyl, decyl or ethyl; Or
(k) R represents ethyl.
The pharmacology result
Data in the body of following rat, dog and monkey, exemplary illustration monoesters prodrug of the present invention with respect to (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-counts the improvement of acid aspect bioavailability.
Adopt following equation to calculate bioavailability:
Wherein AUC represents below the curved surface long-pendingly, and on behalf of dosage forms for oral administration and i.v., p.o. represent intravenously to use.
Bioavailability in the dog body
Beagle dog (2 male and 1 female), per os, then iv give (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (10mg/Kg, p.o; 1mg/Kg, i.v.), in order to measure oral administration biaavailability.Subsequently, 3 same dog per os give the 10mg/kg ester prodrugs (for example (and 3S, 4aR, 6R, 8aR)-6-[2 ((2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester, hydrochloride), whether improve the bioavailability of parent acid in order to determine prodrug.Adopt LC/MS/MS, measure (3S, 4aR, 6R, 8aR)-6-[2 (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the plasma concentration of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid.
Research method:
Live Phase: will (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (HCl salt) is dissolved in (30mg/ml) in the dilute sodium hydroxide, for oral; It is dissolved in (10mg/ml) in 10% ethanol/water, for the iv administration.Will (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-ethyl isoquinoline-3-carboxylate (hydrochloride) (30mg/ml) soluble in water is for oral.The heavy 12-15kg of dog.
The result:
(3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, the 8a-decahydro-isoquinoline 99.9-oral administration biaavailability of 3-carboxylic acid in dog is 18%.And use (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, behind 8a-decahydro-ethyl isoquinoline-3-carboxylate (hydrochloride), bioavailability increases to 33.1%.Compare with parent acid, and prodrug forms (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the bioavailability of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester (hydrochloride) increases by 2 times.
Following table 1 has been summed up the medicine kinetic parameter behind Beagle dog administered compound A and B 1mg/kg (i.v.) or the 10mg/kg (p.o.).
Table 1.Beagle dog administered compound A (1mg/kg, i.v.) and compound
A (10mg/kg, p.o.) or the pharmacokinetic parameter behind the ethyl ester prodrug compd B (p.o.)
| Compound | T max(hr) | C max(ng/mL) | AUC (ng?hr/mL) | The % bioavailability | Improve |
| A (acid), i.v. (1mg/kg) | - | 2.820 | 4.220 | - | - |
| A (acid), p.o. (10mg/kg) | 4 | 1.227 | 7.577 | 18.0 | 1 |
| B (ester), p.o. (10mg/kg) | 4 | 1.662 | 13.953 | 33.1 | ～2X |
Bioavailability in the rat body
Male Fischer rat, per os or iv give (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (30mg/Kg, p.o; 10mg/Kg, i.v.), in order to measure oral administration biaavailability.Another group rat oral give the 10mg/kg ester prodrugs (for example (and 3S, 4aR, 6R, 8aR)-6-[2 ((2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester, hydrochloride), whether improve the bioavailability of parent acid in order to determine prodrug.Adopt LC/MS/MS, measure (3S, 4aR, 6R, 8aR)-6-[2 (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the plasma concentration of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid.
Research method:
Live Phase: will (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (HCl salt) is dissolved in (15mg/ml) in the dilute sodium hydroxide, for oral; It is dissolved in (10mg/ml) in 10% ethanol/water, for the iv administration.Will (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-ethyl isoquinoline-3-carboxylate's hydrochloride (15mg/ml) soluble in water is for oral.Totally 344 Fischer rats, body weight 218-244g.Gathered plasma sample (3 rats of each time point) in 0.5,1,2,4,6,8,10 and 24 hour.
The result:
(3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, the 8a-decahydro-isoquinoline 99.9-oral administration biaavailability of 3-carboxylic acid in rat is 3.6%.And use (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, behind 8a-decahydro-ethyl isoquinoline-3-carboxylate (hydrochloride), bioavailability increases to 17.7%.Compare with parent acid, and prodrug forms (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the bioavailability of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester (hydrochloride) increases by 500 approximately.
Following table 2 has been summed up the medicine kinetic parameter behind Fischer rat administered compound A and B10mg/kg (i.v.) or the .30mg/kg (p.o.).
Table 2.Fischer rat administered compound A (10mg/kg.) or ester prodrugs compd B *
After pharmacokinetic parameter
| Compound | ??T max??(hr) | ??C max??(ng/mL) | ??????AUC ????(ng?hr/mL) | The % bioavailability | Improve |
| A (acid), i.v. (10mg/kg) | ??- | ??11.022 | ????6.727 | ????- | |
| A (acid), p.o. (30mg/kg) | ??93 | ????241 | ????3.6 | ??1 | |
| B (ester), p.o. (30mg/kg) | ??265 | ????1.192 | ????17.7 | ??～5X |
Bioavailability in the stump-tailed macaque body
2 male and 2 female stump-tailed macaques, per os, then iv give (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (3mg/Kg, p.o; 0.3mg/Kg, i.v.), in order to measure oral administration biaavailability.Same animal per os give 3mg/kg (3S, 4aR, 6R, 8aR)-6-[2 ((2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, whether 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester improves the bioavailability of parent acid in order to determine prodrug.Adopt LC/MS/MS, measure plasma concentration
Research method:
4 stump-tailed macaques (every kind sex 2), gave in 0 day single oral dose (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8,8a-Decahydroisoquinolinpreparation-3-carboxylic acid (3mg/kg); Gave in the 4th day the iv single dose (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid (0.3mg/kg); With gave in the 8th day single oral dose (3S, 4aR, 6R, 8aR)-6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-ethyl isoquinoline-3-carboxylate (3mg/kg).After oral 0.5,1,2,3,4,5,6 and 8 hour, after 0.167,0.33,0.67,1,1.5,2,3 and 4 hour, gather plasma sample in the iv administration.In 0.9% sodium-chlor, prepare the drug solns of giving of described acid and ester.
The result:
(3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, the 8a-decahydro-isoquinoline 99.9-oral administration biaavailability of 3-carboxylic acid in stump-tailed macaque is 4.5%.And use (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl)-ethyl-1,2,3,4,4a, 5,6,7,8, behind 8a-decahydro-ethyl isoquinoline-3-carboxylate (hydrochloride), bioavailability increases to 11.4%.Compare with parent acid, and prodrug forms (3S, 4aR, 6R, 8aR)-and 6-[2-(1 (2) H-tetrazolium-5-yl) ethyl-1,2,3,4,4a, 5,6,7,8, the bioavailability of 8a-Decahydroisoquinolinpreparation-3-carboxylic acid, ethyl ester (hydrochloride) increases by 2.5 times approximately.
Following table 3 has been summed up the medicine kinetic parameter behind stump-tailed macaque i.v. or p.o. administered compound A and the B.
Medicine behind table 3. stump-tailed macaque i.v. and p.o. administered compound A or the ester prodrugs compd B
The thing kinetic parameter
| Compound | ??T max??(hr) | ???C max??(ng/mL) | ?????AUC ??(ng?hr/mL) | The % bioavailability | Improve |
| A (acid), i.v. (3mg/kg) | ??- | ??1.622 | ????1.076 | ????- | |
| A (acid), p.o.3mg/kg) | ??6 | ??77 | ????479 | ????4.5 | ??1 |
| B (ester), p.o. (3mg/kg) | ??2 | ??301 | ????1225 | ????11.4 | ??～2.5X |
The present invention further provides antagonism AMPA or GluR
5The method of acceptor (excitatory amino acid receptor that belongs to a big class) comprises that the formula I compound with significant quantity gives the patient.Excessive or inadequate stimulus to excitatory amino acid receptor can cause neurocyte to damage or lose because of known excitotoxicity mechanism.This process prompting mediates neuronal degeneration in nervous system disorders and disorder.The effect of this neuronal degeneration that medicine is right promptly alleviates sex change neuroscience process, is important therapeutic goal.For example, the excitatory amino acid receptor excitotoxicity is relevant with the physiopathology of many neurological disorders, comprising: the etiology of Spinal injury, perinatal hypoxia, cardiac arrest and hypoglycemia neuronal damage due to heart bypass operation and posttransplantation brain defective, apoplexy, cerebral ischemia, hurt or the inflammation.In addition, excitotoxicity is relevant with chronic neurodegenerative conditions, comprising: the dementia that Alzheimer disease, Huntington tarantism, hereditary ataxia, AIDS bring out, amyotrophic lateral sclerosis, spontaneous and drug-induced Parkinson disease and ocular damage and retinopathy.Other neurological disorder relevant with excitotoxicity and/or glutamate abnormality comprises: comprise tremble, the muscular rigidity of resistance and withdrawal symptom, cerebral edema, convulsive disorder comprises epilepsy, and melancholia stress syndromes after anxiety and the illness relevant with anxiety are for example traumatic, tardive dyskinesia, with with melancholia, schizophrenia, bipolar disorder, psychosis that mania is relevant, with drug intoxication or habituation (can be referring to United States Patent (USP) 5,446,051 and 5,670,516).The excitatory amino acid receptor antagonist can be used as pain killer, is used for the treatment of or prevents various forms of headaches, comprises cluster headache, tension-type headache and chronic every day of headache.In addition, the etiology of the open WO98/45720 report of international monopoly excitatory amino acid receptor excitotoxicity and acute and chronic pain state (comprise serious pain, intractable pain, neuropathic pain, wound after pain) is relevant.
Also known gasserian ganglion and related neural passage thereof are relevant with the pain (for example headache and especially migraine) of head and face at present.Moskowitz (Cephalalgia, 12,5-7, (1992)) proposes the stimulation of unknown triggering to gasserian ganglion (otherwise the vascular system in the domination head tissue), causes the vasoactive neuropeptide to discharge from the aixs cylinder of domination vascular system.These neuropeptides have triggered a series of variations that can cause meningeal neurogenic inflammation, consequently pain.Treat the sumatriptan of people's acute migraine amount, can stop this neurogenic inflammation.Yet because sumatriptan is attended by the vasoconstriction effect, the sumatriptan of this dosage has certain contraindication.(referring to Maclntyre, P.D. etc., British Journal of Clinical Pharmacology, 34,541-546 (1992); Chester, A.H. etc., Cardiovascular Research, 24,932-937 (1990); Conner, H.E. etc., European Journal of Pharmacology, 161,91-94 (1990)).Recently, have and report 5 kinds of kainic acids (kainate) hypotype of on the rat trigeminal ganglion neuron, having expressed ionic channel type glutamate receptor, especially observe high-caliber GluR
5And KA2 (Sahara etc., The Journal of Neuroscience, 17 (17), 6611 (1997)).Thereby migraine shows as the another kind of neurological disorder relevant with the glutamate receptor excitotoxicity.
It is believed that for example excitatory amino acid receptor antagonist of neuroprotective, can be used for treating or preventing all above-mentioned illnesss and/or lower the neurological damage degree relevant with these illnesss.For example, studies show that the ampa receptor antagonist has neuroprotective in focus with whole-heartedly in (global) ischemia model.Report competitive ampa receptor antagonist NBQX (2,3-dihydroxyl-6-nitro-7-sulphonamide benzo [f] quinoline) preventive effect property and focus ischemia damage whole-heartedly in advance.Sheardown etc., Science, 247,571 (1900); Buchan etc., Neuroreport, 2,473 (1991); LePeillet etc., Brain Research, 571,115 (1992).Verified, noncompetitive ampa receptor antagonist GKYI 52466 is effective neuroprotective in rat global ischemia model.LaPeillet etc., BrainResearch, 571,115 (1992).It is AMPA that open 590789A1 of european patent application and United States Patent (USP) 5,446,051,5,670,516 disclose some Decahydroisoquinolinpreparation derivative, therefore can be used for treating numerous disease state for example pain and migraine.It is iGluR that WO98/45270 discloses the Decahydroisoquinolinpreparation derivative
5The selectivity antagonist of acceptor, can be used for treating various types of pain for example violent, chronic, intractable and neuropathic pain.
Thereby as discussed above, The compounds of this invention can be used for treating neurological disorder.This compound can satisfy for a long time the security of neurotherapy and the demand of validity, and the side effect of not following.In addition, the present invention further provides the method that is used for the treatment of neurological disorder, comprise the patient who the formula I compound of significant quantity is given this is had needs.More particularly, the present invention further provides and be used for the treatment of pain or migrainous method, comprise the patient who the formula I compound of significant quantity is given this is had needs.Help promoting treatment to neurological disorder and neurodegenerative disease.
Be meant Mammals at this used term " patient ", for example mouse, cavy, rat, dog, monkey or people.Be understandable that preferably people of described patient.
Comprise its general implication at this used term " processing " (or " treatment "), promptly stop, prevent, suppress and slow down, stop or reversing the course of disease, the seriousness of corresponding symptom.Thereby the inventive method comprises treatment and preventive administration.
Be meant that in this used " significant quantity " amount that is administered to patient's compound through list or multiple doses can produce desired result.
Adopt known technology and utilization to the observations under the similar state, those skilled in the art are that the attending doctor is easy to determine described significant quantity.When determining the significant quantity dosage of administered compound, many factors that the attending doctor should consider include but not limited to: mammiferous species; Size, age and general health situation; Related disease specific; The degree of described disease or complicacy or seriousness; The reaction of individual patient; The specific compound of being used; Administering mode; The bioavailability characteristics of preparation; Dosage regimen; Using of the other drug same period; And other relevant situation.
Typical per daily dose comprises the active compound of the present invention of about 0.01mg/kg-100mg/kg.Preferably, per daily dose is about 0.05mg/kg-50mg/kg, about 0.1mg/kg-25mg/kg.
When effectively treatment suffered from the patient of above-mentioned disorder, disease or obstacle, the form mode that can anyly can form the biological activity parent monoprotic acid compound of significant quantity was used formula (I) compound, comprises oral and non-enteron aisle path.For example, but oral administration, subcutaneous, intramuscular, intravenously, approach such as rectum, cheek are used formula (1) compound in skin (transdennally), nose.In addition, also can give compound through continuous infusion.General preferred oral.According to the characteristic of described compound, morbid state to be treated, degree and other relevant situation of disease, the those of ordinary skill in pharmaceutical technology field can be selected suitable administration form and mode at an easy rate,
It will be appreciated by persons skilled in the art that all compounds that the present invention uses all can salify, and described pharmaceutical salts is normally operable, this is because easier crystallization of common specific ionization alkali of these pharmaceutical salts and purifying.In all cases, can use the salt of said medicine, and this is preferred usually, the title of all compounds all comprises its pharmacologically acceptable salt.
The present invention provides pharmaceutical composition on the other hand, comprising formula I compound or pharmaceutically acceptable salt thereof and medicinal diluent or carrier as defined above.
Can adopt the composition of known and easy acquisition, through the currently known methods pharmaceutical compositions.When producing the present composition, described activeconstituents usually and mixed carrier or with the carrier dilution, or is sealed with carrier, can be capsule, sachet, charta (paper) or other vessel form.When carrier is used as thinner, can be solid, semisolid or fluent material as carrier for active principle, vehicle or medium.
Described composition can be the powder of tablet, pill, powder, lozenge, sachet, flat capsule, elixir, suspensoid, emulsion, solution, syrup, aerosol, the ointment that contains for example maximum 10% weight active compounds, soft hard capsule, suppository, sterile injectable solution and sterile packed.
The example of appropriate carrier, vehicle and thinner comprises: lactose, glucose, sucrose, Sorbitol Powder, mannitol, starch, natural gum, gum arabic, calcium phosphate, alginate, tragacanth (tragcanth), gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, aqueous syrup agent (water syrup), methylcellulose gum, Tegosept M and propylben, talcum, Magnesium Stearate and mineral oil.Described preparation also can comprise lubricant, wetting agent, emulsifying agent and suspending agent, sanitas, sweeting agent or seasonings.Adopt means known in the art, the present composition can be made the formulation of using back quick-release, slowly-releasing or delayed release of active elements.
Composition is preferably made unit dosage, and each agent comprises about 1mg-500mg, more preferably from about the activeconstituents of 5mg-300mg (for example 25mg).Term " unit dosage " is meant and suits to give experimenter and other mammiferous physically discontinuous unit with unit dosage form, every unit comprises the active substance and suitable pharmaceutical carrier, thinner or the vehicle of the predetermined amount that can produce required therapeutic action.These prescriptions are intended to explanation, and the present invention is acted on without limits.
Preparation 1
Adopt following ingredients to prepare hard capsule:
| Consumption (mg/ capsule) | |
| Prodrug | ????250 |
| Starch, drying | ????200 |
| Magnesium Stearate | ????10 |
| Amount to | ????460 |
Mix in the mentioned component (460mg) and the hard capsule of packing into.
Preparation 2
Be prepared as follows every tablet of tablet that contains the 60mg activeconstituents:
| Consumption (mg/ capsule) | |
| Prodrug | ????60 |
| Starch | ????45 |
| Microcrystalline Cellulose | ????35 |
| Povidone | ????4 |
| Xylo-Mucine | ????4.5 |
| Magnesium Stearate | ????0.5 |
| Talcum powder | ????1 |
| Amount to | ????150 |
Activeconstituents, starch and Mierocrystalline cellulose are crossed 45 order US sieve, and thorough mixing.With polyvinylpyrrolidonesolution solution and gained powder mixes, cross 14 order US sieve then.The gained particle is in 50 ℃ of dryings, and 18 order US sieve excessively.Sodium starch glycolate, Magnesium Stearate and talcum are crossed 60 order US sieve, add to then in the particle, stir the back is pressed into every heavy 150mg on tabletting machine tablet.
Claims (25)
1. following formula: compound:
Wherein R represents C
1-C
20Alkyl, C
2-C
6Alkenyl, C
1-C
6Alkylaryl, C
1-C
6Alkyl (C
3-C
10) cycloalkyl, C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine, C
1-C
6Alkyl-tetramethyleneimine, C
1-C
6Alkyl-piperidines, C
1-C
6Alkyl-morpholine, or its pharmacologically acceptable salt.
2. according to the compound of claim 1, wherein R represents C
1-C
10Alkyl.
3. according to the compound of claim 2, wherein R represents 2-ethyl-butyl, isobutyl-, 3-methyl butyl, decyl or ethyl.
4. according to the compound of claim 3, wherein R represents the 2-ethyl-butyl.
5. according to the compound of claim 3, wherein R represents isobutyl-.
6. according to the compound of claim 3, wherein R represents the 3-methyl butyl.
7. according to the compound of claim 3, wherein R represents decyl.
8. according to the compound of claim 3, wherein R represents ethyl.
Compound (3S, 4aR, 6R, 8aR)-6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid 2-ethyl-butyl ester, or its pharmacologically acceptable salt.
10. according to the compound of claim 9, wherein pharmacologically acceptable salt is a trifluoroacetate.
11. compound (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid isobutyl ester, or its pharmacologically acceptable salt.
12. according to the compound of claim 11, wherein pharmacologically acceptable salt is a trifluoroacetate.
13. compound (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid 3-methyl butyl ester, or its pharmacologically acceptable salt.
14. according to the compound of claim 13, wherein pharmacologically acceptable salt is a trifluoroacetate.
15. compound (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-isoquinoline 99.9-3-carboxylic acid ester in the last of the ten Heavenly stems, or its pharmacologically acceptable salt.
16. according to the compound of claim 15, wherein pharmacologically acceptable salt is a trifluoroacetate.
17. compound (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-ethyl isoquinoline-3-carboxylate, or its pharmacologically acceptable salt.
18. according to the compound of claim 15, wherein pharmacologically acceptable salt is a hydrochloride.
19. compound (3S, 4aR, 6R, 8aR)-and 6-[2-(1H-tetrazolium-5-yl)-ethyl]-1,2,3,4,4a, 5,6,7,8,8a-decahydro-ethyl isoquinoline-3-carboxylate's hydrochloride mono-hydrate.
20. a pharmaceutical composition is comprising the described compound of claim 1 and medicinal diluent or carrier.
21. one kind is used for the treatment of pain or migrainous pharmaceutical composition, comprising the described compound of claim 1 and medicinal diluent or carrier.
22. the method for treatment pain comprises that the following formula: compound with significant quantity gives the patient
Wherein R represents C
1-C
20Alkyl, C
2-C
6Alkenyl, C
1-C
6Alkylaryl, C
1-C
6Alkyl (C
3-C
10) cycloalkyl, C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine, C
1-C
6Alkyl-tetramethyleneimine, C
1-C
6Alkyl-piperidines, C
1-C
6Alkyl-or its pharmacologically acceptable salt.
23. treat migrainous method, comprise that the following formula: compound with significant quantity gives the patient:
Wherein R represents C
1-C
20Alkyl, C
2-C
6Alkenyl, C
1-C
6Alkylaryl, C
1-C
6Alkyl (C
3-C
10) cycloalkyl, C
1-C
6Alkyl-N, N-C
1-C
6Dialkylamine, C
1-C
6Alkyl-tetramethyleneimine, C
1-C
6Alkyl-piperidines, C
1-C
6Alkyl-or its pharmacologically acceptable salt.
24. the described compound of claim 1 is used for the treatment of application in the medicine of pain in preparation.
25. the described compound of claim 1 is used for the treatment of application in the migrainous medicine in preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37612002P | 2002-04-26 | 2002-04-26 | |
| US60/376,120 | 2002-04-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1649862A true CN1649862A (en) | 2005-08-03 |
| CN100436446C CN100436446C (en) | 2008-11-26 |
Family
ID=29270765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038094606A Expired - Fee Related CN100436446C (en) | 2002-04-26 | 2003-04-14 | Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics |
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| Country | Link |
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| US (1) | US7247644B2 (en) |
| EP (1) | EP1511741B1 (en) |
| JP (2) | JP2005529892A (en) |
| KR (1) | KR100757787B1 (en) |
| CN (1) | CN100436446C (en) |
| AU (1) | AU2003226277B2 (en) |
| BR (1) | BR0308911A (en) |
| CA (1) | CA2480026C (en) |
| DK (1) | DK1511741T3 (en) |
| EA (1) | EA009526B1 (en) |
| ES (1) | ES2398225T3 (en) |
| IL (1) | IL164773A (en) |
| MX (1) | MXPA04009857A (en) |
| NZ (1) | NZ535245A (en) |
| PT (1) | PT1511741E (en) |
| SI (1) | SI1511741T1 (en) |
| WO (1) | WO2003091243A1 (en) |
| ZA (1) | ZA200409552B (en) |
Families Citing this family (5)
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|---|---|---|---|---|
| PT1511741E (en) * | 2002-04-26 | 2013-02-05 | Lilly Co Eli | Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics |
| WO2008088820A2 (en) | 2007-01-16 | 2008-07-24 | The Johns Hopkins University | Glutamate receptor antagonists and methods of use |
| AU2021299570A1 (en) * | 2020-07-02 | 2023-02-23 | Sea Pharmaceuticals Llc | Pharmaceutical compositions of 6-(2-(2H-tetrazol-5-yl)ethyl)-6-fluorodecahydroisoquinoline-3-carboxylic acid and ester derivatives thereof |
| EP4352047A1 (en) * | 2021-06-09 | 2024-04-17 | Proniras Corporation | Methods of treating nerve agent-induced seizures |
| WO2023130008A2 (en) * | 2022-01-01 | 2023-07-06 | Sea Pharmaceuticals Llc | Pharmaceutical compositions of 6-(2-(2h-tetrazol-5-yl)ethyl)decahydroisoquinoline-3-carboxylic acid and derivatives thereof |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK406686D0 (en) * | 1986-08-26 | 1986-08-26 | Hans Bundgaard | carboxylic acid derivatives |
| US4902695A (en) | 1989-02-13 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US5284957A (en) * | 1992-09-03 | 1994-02-08 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US5356902A (en) | 1992-11-06 | 1994-10-18 | Eli Lilly And Company | Decahydroisoquinoline compounds as excitatory amino acid receptor antagonists |
| US5446051A (en) | 1994-05-31 | 1995-08-29 | Eli Lilly And Company | Aryl-spaced decahydroisoquinoline-3-carboxylic acids as excitatory amino acid receptor antagonists |
| US5767117A (en) | 1994-11-18 | 1998-06-16 | The General Hospital Corporation | Method for treating vascular headaches |
| KR20010006075A (en) | 1997-04-07 | 2001-01-15 | 피터 지. 스트링거 | Pharmacological Agents |
| PT1200073E (en) | 1999-07-06 | 2007-03-30 | Lilly Co Eli | Selective iglur 5? receptor antagonists for the treatment of migraine |
| EP1208087B1 (en) * | 1999-07-06 | 2003-05-14 | Eli Lilly And Company | Diester prodrugs of a decahydroisoquinoline-3-carboxylic acid |
| EP1257545A1 (en) | 1999-12-22 | 2002-11-20 | Eli Lilly And Company | SELECTIVE iGLUR 5? RECEPTOR ANTAGONISTS |
| AU2001298029A1 (en) | 2001-01-05 | 2003-04-01 | Eli Lilly And Company | Derivatives of the (3s, 4ar, 6s, 8ar) 6-phenylamino-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydro isoquinoline-3-carboxylic acid as excitatory amino acid receptor antagonists for the treatment of neurological disorders and neurodegenerative diseases |
| US6953805B2 (en) | 2001-01-05 | 2005-10-11 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US6855725B2 (en) | 2001-01-05 | 2005-02-15 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| WO2003024453A1 (en) | 2001-01-05 | 2003-03-27 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| WO2003082856A1 (en) | 2002-03-22 | 2003-10-09 | Eli Lilly And Company | Isoquinoline-3-carboxylic acid derivatives as excitatory amino acid receptor antagonists |
| PT1511741E (en) * | 2002-04-26 | 2013-02-05 | Lilly Co Eli | Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics |
-
2003
- 2003-04-14 PT PT37472693T patent/PT1511741E/en unknown
- 2003-04-14 CN CNB038094606A patent/CN100436446C/en not_active Expired - Fee Related
- 2003-04-14 EA EA200401432A patent/EA009526B1/en not_active IP Right Cessation
- 2003-04-14 WO PCT/US2003/010466 patent/WO2003091243A1/en active Application Filing
- 2003-04-14 NZ NZ535245A patent/NZ535245A/en not_active IP Right Cessation
- 2003-04-14 DK DK03747269.3T patent/DK1511741T3/en active
- 2003-04-14 JP JP2003587801A patent/JP2005529892A/en active Pending
- 2003-04-14 BR BR0308911-8A patent/BR0308911A/en active Search and Examination
- 2003-04-14 MX MXPA04009857A patent/MXPA04009857A/en active IP Right Grant
- 2003-04-14 US US10/511,452 patent/US7247644B2/en not_active Expired - Fee Related
- 2003-04-14 EP EP03747269A patent/EP1511741B1/en not_active Expired - Lifetime
- 2003-04-14 SI SI200332227T patent/SI1511741T1/en unknown
- 2003-04-14 CA CA2480026A patent/CA2480026C/en not_active Expired - Fee Related
- 2003-04-14 AU AU2003226277A patent/AU2003226277B2/en not_active Ceased
- 2003-04-14 ES ES03747269T patent/ES2398225T3/en not_active Expired - Lifetime
- 2003-04-14 KR KR1020047017143A patent/KR100757787B1/en not_active IP Right Cessation
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2004
- 2004-10-21 IL IL164773A patent/IL164773A/en not_active IP Right Cessation
- 2004-11-25 ZA ZA200409552A patent/ZA200409552B/en unknown
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- 2010-06-23 JP JP2010142881A patent/JP2010235623A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| PT1511741E (en) | 2013-02-05 |
| CA2480026A1 (en) | 2003-11-06 |
| AU2003226277A1 (en) | 2003-11-10 |
| JP2010235623A (en) | 2010-10-21 |
| DK1511741T3 (en) | 2013-01-21 |
| MXPA04009857A (en) | 2004-12-07 |
| IL164773A0 (en) | 2005-12-18 |
| IL164773A (en) | 2011-08-31 |
| ES2398225T3 (en) | 2013-03-14 |
| WO2003091243A8 (en) | 2005-03-31 |
| US7247644B2 (en) | 2007-07-24 |
| EA009526B1 (en) | 2008-02-28 |
| CN100436446C (en) | 2008-11-26 |
| ZA200409552B (en) | 2006-02-22 |
| KR100757787B1 (en) | 2007-09-11 |
| CA2480026C (en) | 2011-06-07 |
| SI1511741T1 (en) | 2013-02-28 |
| WO2003091243A1 (en) | 2003-11-06 |
| JP2005529892A (en) | 2005-10-06 |
| EA200401432A1 (en) | 2005-04-28 |
| EP1511741A1 (en) | 2005-03-09 |
| NZ535245A (en) | 2007-11-30 |
| EP1511741B1 (en) | 2012-12-26 |
| BR0308911A (en) | 2005-01-04 |
| KR20040102171A (en) | 2004-12-03 |
| US20050256155A1 (en) | 2005-11-17 |
| AU2003226277B2 (en) | 2009-03-26 |
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